Familially Inherited Sitosterolemia in Pediatric Siblings: A Detailed Case Study and Literature Review

Introduction

Sitosterolemia, also known as phytosterolemia, is a rare, autosomal recessive lipid metabolism disorder characterized by elevated plasma and tissue sitosterol levels. This condition arises from increased intestinal absorption and reduced biliary excretion of plant sterols. Clinically, sitosterolemia manifests through xanthomas, premature atherosclerosis, and a spectrum of cardiovascular symptoms including angina pectoris, myocardial infarction, and intermittent claudication. Arthritis, arthralgia, and hemolytic abnormalities can also occur. While over 100 genetically confirmed cases have been reported globally, the genetic underpinnings differ geographically. Asian populations predominantly exhibit mutations in the adenosine triphosphate-binding cassette transporter G family member 5 (ABCG5) gene, whereas Caucasian patients more frequently have mutations in the ABCG8 gene. Advancements in genetic diagnostics have facilitated increased recognition and reporting of sitosterolemia, including within China. This case report details the diagnosis and management of two siblings, a brother and sister, presenting with sitosterolemia and prominent multiple xanthomas, managed at the Burn and Plastic Surgery department. This Familially inherited condition highlights the importance of genetic screening and tailored treatment strategies in managing rare lipid disorders.

Case Report

Case 1

The first patient was a 9-year-old male, the elder sibling of Case 2. Crucially, both parents, while carriers of the mutated gene, were asymptomatic, emphasizing the recessive nature of this familially transmitted disorder. He presented to Dalang Hospital of Dongguan (DHD) with masses on his buttocks and extremities, which had been present for four years.

Case History

His medical journey, summarized in Table 1, began in July 2017 when he was evaluated at Guangzhou Women and Children’s Medical Center (GWCMC) for “masses in the limbs and buttocks.” Examination revealed multiple xanthomas across his buttocks and limb joints. Initial laboratory findings (Table 2) demonstrated significantly elevated serum total cholesterol (TC) at 15.13 mmol/L, serum triglyceride (TG) at 1.95 mmol/L, high-density lipoprotein cholesterol (HDL-C) at 1.99 mmol/L, low-density lipoprotein cholesterol (LDL-C) at 14.04 mmol/L, apolipoprotein B (Apo B) at 3.08 g/L, apolipoprotein E (APOE) at 95.4 mg/L, and free fatty acids (FFAS) at 1.4 mmol/L. Repeated testing confirmed these elevated lipid parameters. A mass biopsy confirmed xanthoma, and while lipid-lowering treatment was initiated, the xanthomas continued to enlarge.

[Table 1. Basic information of Case 1 from onset to date.

Basic information timeline of Case 1 from disease onset to diagnosis and treatment, detailing key medical events, diagnoses, and interventions

[Table 2. Blood lipid levels before and after lipid-lowering treatment.

Comparison of blood lipid levels in Case 1 before and after lipid-lowering treatment, illustrating changes in cholesterol, triglycerides, and lipoproteins

In April 2020, he was admitted to the Department of Pediatrics at the First Affiliated Hospital of Sun Yat-sen University (FAHSU) for “multiple skin xanthomas and arrhythmia for over two years.” Physical examination revealed: T=37°C, P=110 bpm, R=24 breaths/min, right upper limb BP=84/65 mmHg, right lower limb BP=102/64 mmHg, left upper limb BP=95/60 mmHg, left lower limb BP=96/48 mmHg, and weight=19.6 kg. He exhibited growth retardation and widespread yellowish-brown, soft nodules, characteristic of xanthomas, particularly prominent around large joints. Xanthelasmas were noted on both upper eyelids. Cardiac examination revealed a heart rate of 110 bpm, an irregular rhythm with premature beats, and strong heart sounds without murmurs. Laboratory results showed: TC=4.5 mmol/L, TG=0.57 mmol/L, HDL-C=0.84 mmol/L, LDL-C=3.05 mmol/L, serum C-reactive protein=41.78 mg/L, erythrocyte sedimentation rate=81 mm/h, interleukin 6=23.26 pg/mL, and albumin=38.2 g/L. Arterial Doppler ultrasonography indicated Takayasu’s arteritis signs, subclavian artery stenosis with partial steal syndrome, bilateral common carotid artery stenosis, abdominal aortic wall thickening and stenosis, and proximal bilateral renal artery narrowing. ECG revealed frequent junctional premature beats, paroxysmal supraventricular tachycardia, and occasional premature ventricular contractions.

Genetic testing for hyperlipidemia, conducted at Guangzhou KingMed Diagnostics Center in April 2020, identified a splice mutation in intron 7 and intron 9 of chromosome 2p21 within the ABCG5 gene. Parental testing confirmed the familial inheritance pattern: the mother carried the heterozygous variant at intron 7, and the father carried the heterozygous variant at intron 9 (Table 3).

[Table 3. Whole-exome sequencing results showing compound heterozygous mutations in the ABCG5 gene for both Case 1 and Case 2.

Genetic analysis results showing compound heterozygous mutations in ABCG5 gene for both siblings, highlighting specific intron mutations and parental origins

The final diagnoses were: (1) hereditary sitosterolemia, a familially transmitted condition; (2) multiple arterial stenosis; (3) arrhythmia; and (4) moderate growth retardation. Treatment commenced with ezetimibe for lipid lowering and clopidogrel bisulfate (Talcom) for anticoagulation. While the xanthomas on his buttocks softened, significant shrinkage was not observed.

Examination Results

In July 2021, the patient presented to the outpatient clinic at DHD for xanthoma on his buttocks.

Physical Examination

Physical examination revealed: T=36.2°C, P=84 bpm, R=20 breaths/min, and BP=102/53 mmHg. Xanthelasmas were still present on both upper eyelids (Figure 1A). Large, round masses, measuring 7 × 8 cm and 8 × 8 cm respectively, were noted on his buttocks, protruding without ulceration (Figure 1B). Partial shrinkage of knee joint xanthomas was observed following drug treatment (Figure 1C). Surgical scar tissue from previous xanthoma excisions on both elbows was evident (Figures 1D,E).

[Figure 1. Case 1 clinical features and surgical outcomes. (A) Xanthelasmas on the eyelids, a common sign of sitosterolemia. (B) Buttocks xanthoma before surgical removal, demonstrating the size and prominence of the lesions. (C) Partial xanthoma shrinkage in knee joints after lipid-lowering therapy, showing medication effectiveness. (D) Left elbow surgical scar one year post-xanthoma resection, indicating healing and cosmetic outcome. (E) Right elbow surgical scar one year post-xanthoma resection, mirroring the left elbow’s healing. (F) Excised xanthoma tissue during surgery, displaying the characteristic yellowish nodular appearance. (G) Buttocks appearance six months post-xanthoma resection, demonstrating successful surgical removal and healing.

Clinical images of Case 1 showing xanthelasma, buttocks xanthoma, xanthoma shrinkage with medication, elbow surgery scars, excised xanthoma tissue, and post-surgical outcome

Other Examinations

ECG showed sinus arrhythmia and frequent premature atrial contractions (Figure 2). Laboratory tests (Table 2) revealed: TC=6.19 mmol/L, TG=1.39 mmol/L, HDL-C=1.15 mmol/L, and LDL-C=2.85 mmol/L.

[Figure 2. ECG of Case 1 illustrating cardiac arrhythmia. The electrocardiogram tracing shows sinus arrhythmia and frequent premature atrial contractions, indicating cardiac involvement in sitosterolemia.

Electrocardiogram of Case 1 demonstrating sinus arrhythmia and premature atrial contractions, reflecting cardiovascular complications

Therapeutic Intervention and Outcomes

Surgical resection of the buttocks xanthomas was performed under general anesthesia. The masses were characterized as brownish-yellow nodules, primarily located near joints and pressure points, with distinct boundaries and a soft texture. Incision and dissection revealed the masses to be within the superficial fascia, lacking a capsule, with a pale-yellow, tough cut surface (Figure 1F). Microscopic examination confirmed tuberous xanthoma, composed of foamy histiocytes, multinucleated macrophages, and proliferating fibrous tissue. Postoperative healing was primary and uneventful.

Lipid-lowering and anticoagulation therapy with Ezetimibe and clopidogrel, respectively, was continued post-discharge. A 6-month follow-up showed no xanthoma recurrence (Figure 1G). March 2022 laboratory results were: TG=0.84 mmol/L, TC=6.61 mmol/L, HDL-C=1.52 mmol/L, LDL-C=3.81 mmol/L, and Apo B=1.41 g/L. ECG findings remained consistent.

Case 2

The second patient, the younger sister of Case 1, was a 7-year-old female. She was admitted in January 2022 for “bumps on both elbows for over 2 years.” Her family reported progressively growing masses on her elbows, without pain, ulceration, or movement restriction. She was admitted for surgical treatment of these masses. Like her brother, her condition was familially derived.